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Though the events that initiate Parkinson's disease are unclear, mitochondrial defects – together with inflammation and oxidative damage – are believed to be critical factors in the death of dopamine neurons as the disease progresses. Now new research from P&S neurologists suggests that the death of many neurons during Parkinson's disease can be prevented with a molecule that revs up the neurons' mitochondria. The study appears in the Sept. 15 issue of the Journal of Clinical Investigation.
In people with Parkinson's, mitochondria in the dopamine neurons are sluggish, producing fewer than the normal number of ATP molecules needed to power the cells. The energy crisis contributes to cell death of dopamine neurons in specific regions of the brain that control motor functions. Loss of neurons and the dopamine they release produce muscle stiffness and tremors. Current therapies for Parkinson's lessen the severity of the disease's symptoms but are unable to slow its progression.
Using mouse models that replicate most of the disease's features, Dr. Serge Przedborski, professor of neurology, and postdoctoral researcher Dr. Kim Tieu found that they could prevent neuronal death in the mice by boosting the production of ATP with a molecule called D-ß-hydroxybutyrate (DßHB), which is normally used as a source of energy in the brain when glucose in unavailable. Mice given DßHB for seven days had twice as many neurons, produced more dopamine, and had less severe physical symptoms than untreated mice.
The drug works by supplying electrons to the mitochondria's electron transport chain, which produces the energy needed to make ATP. Normally, electrons are fed into the chain at two protein complexes, I and II, before flowing through the rest of the chain. In people with Parkinson's, complex I only runs at 60 percent to 70 percent capacity, and with complex I subdued, ATP production slows. DßHB fuels ATP production by supplying electrons to complex II.
Though the researchers saw no side effects in the mice from the short-term use of DßHB they also say it's metabolized too quickly to be used in people. To maintain a constant level of the molecule in the mice, Dr. Tieu had to implant miniature pumps that continually released DßHB under the skins of the animals. Because the pumps aren't feasible for use in humans, clinical use of the molecule may only be possible if alterations to the molecule produce a longer-lasting form. In the meantime, Dr. Przedborski's lab is looking for other molecules that perform like DßHB.
Given the other contributors to neuronal death, the researchers say that DßHB, or other drugs that boost ATP production, may be most effective when combined with drugs that have antioxidant and anti-inflammatory properties. "We don't believe there's a single mechanism that kills neurons, so targeting this one may not mitigate the others," Dr. Przedborski says. "We anticipate better effects would be seen with a cocktail of different drugs." 
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